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The motif composition of variable number tandem repeats impacts gene expression.

ABSTRACT: Understanding the impact of DNA variation on human traits is a fundamental question in human genetics. Variable number tandem repeats (VNTRs) make up ∼3% of the human genome but are often excluded from association analysis owing to poor read mappability or divergent repeat content. Although methods exist to estimate VNTR length from short-read data, it is known that VNTRs vary in both length and repeat (motif) composition. Here, we use a repeat-pangenome graph (RPGG) constructed on 35 haplotype-resolved assemblies to detect variation in both VNTR length and repeat composition. We align population-scale data from the Genotype-Tissue Expression (GTEx) Consortium to examine how variations in sequence composition may be linked to expression, including cases independent of overall VNTR length. We find that 9422 out of 39,125 VNTRs are associated with nearby gene expression through motif variations, of which only 23.4% are accessible from length. Fine-mapping identifies 174 genes to be likely driven by variation in certain VNTR motifs and not overall length. We highlight two genes, CACNA1C and RNF213, that have expression associated with motif variation, showing the utility of RPGG analysis as a new approach for trait association in multiallelic and highly variable loci.

SUBMITTER: Lu TY

PROVIDER: S-EPMC10234305 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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The motif composition of variable number tandem repeats impacts gene expression.

Lu Tsung-Yu TY Smaruj Paulina N PN Fudenberg Geoffrey G Mancuso Nicholas N Chaisson Mark J P MJP

Genome research 20230410 4

Understanding the impact of DNA variation on human traits is a fundamental question in human genetics. Variable number tandem repeats (VNTRs) make up ∼3% of the human genome but are often excluded from association analysis owing to poor read mappability or divergent repeat content. Although methods exist to estimate VNTR length from short-read data, it is known that VNTRs vary in both length and repeat (motif) composition. Here, we use a repeat-pangenome graph (RPGG) constructed on 35 haplotype- ...[more]

PMID: 37037626

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Project description:Immunity and cytokines serve crucial roles in cutaneous melanoma. The present study investigated whether a variable number tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL-1RA) gene (IL-1RN) located in intron 2 (rs2234663) is associated with cutaneous melanoma. A total of 515 subjects were studied, 133 of which were cutaneous melanoma cases (72 stage I+II non-metastatic melanoma cases and 61 stage III+IV metastatic melanoma cases), and 382 subjects were matching healthy controls from the Friuli-Venezia-Giulia Region located in Northeast Italy, an area with a high melanoma incidence. The IL-1RN-VNTR polymorphism was determined by DNA fragment length analysis following PCR amplification. According to the number of 86-bp repeats, five different IL-1RN alleles were identified: Allele 1 (4-repeats), allele 2 (2-repeats, short allele), allele 3 (5-repeats), allele 4 (3-repeats) and allele 5 (6-repeats). Alleles with three or more 86-bp repeats, i.e. allele 1, 3, 4 and 5 were collectively denoted as long (L) repeats. The present study revealed that IL-1RN-VNTR 1/2 and 2/L genotypes were more frequent among patients with cutaneous melanoma (43.6 and 45.1%, respectively) compared with healthy controls [29.6 and 30.6%, respectively; odds ratio (OR), 1.84; CI, 1.22-2.77; P=0.003; and OR, 1.66; CI, 1.24-2.79; P=0.002, respectively]. Conversely, the IL-1RN-VNTR 1/1 genotype was less frequent among melanoma cases (45.9%) compared with healthy controls (57.9%; OR, 0.62; CI, 0.41-0.92; P=0.017). Comparison of metastatic vs. non-metastatic melanoma cases identified no significant differences. The present study first demonstrated that carriage of the 1/1 IL-1RN-VNTR genotype was protective, whereas 1/2 and 2/L was a risk factor for patients with cutaneous melanoma vs. healthy controls. The short allele 2 was associated with higher expression levels of IL-1RA, a potent competitive inhibitor of the proinflammatory cytokines IL-1? and IL-1?. VNTR-IL-1RN polymorphism may affect susceptibility to melanoma and, thus, it is a potential novel diagnostic biomarker for melanoma. The present study increased the understanding of genetic melanoma susceptibility/carcinogenesis, and may indicate novel strategies in the personalized prevention of cutaneous melanoma.

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The motif composition of variable number tandem repeats impacts gene expression.

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The motif composition of variable number tandem repeats impacts gene expression.

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